| 1. |
- de Graan, Anne-Joy M., et al.
(författare)
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Influence of Polymorphic OATP1B-Type Carriers on the Disposition of Docetaxel
- 2012
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 18:16, s. 4433-4440
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii) inherited genetic defects in this process may impair systemic drug elimination.Experimental Design: Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wild-type), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wild-type and Oatp1b2-knockout mice as well as in two cohorts of patients with multiple variant transporter genotypes (n = 213).Results: Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2 but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P = 0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse liver microsomes. In patients, however, none of the studied common reduced function variants in OATP1B1 or OATP1B3 were associated with docetaxel clearance (P > 0.05).Conclusions: The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteins may be required to confer substantially altered disposition phenotypes. In view of the established exposure-toxicity relationships for docetaxel, we suggest that caution is warranted if docetaxel has to be administered together with agents that potently inhibit both OATP1B1 and OATP1B3.
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| 2. |
- de Graan, Anne-Joy M., et al.
(författare)
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A Pharmacogenetic Predictive Model for Paclitaxel Clearance Based on the DMET Platform
- 2013
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:18, s. 5210-5217
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Paclitaxel is used in the treatment of solid tumors and displays high interindividual variation in exposure. Low paclitaxel clearance could lead to increased toxicity during treatment. We present a genetic prediction model identifying patients with low paclitaxel clearance, based on the drug-metabolizing enzyme and transporter (DMET)-platform, capable of detecting 1,936 genetic variants in 225 metabolizing enzyme and drug transporter genes. Experimental Design: In 270 paclitaxel-treated patients, unbound plasma concentrations were determined and pharmacokinetic parameters were estimated from a previously developed population pharmacokinetic model (NONMEM). Patients were divided into a training-and validation set. Genetic variants determined by the DMET platform were selected from the training set to be included in the prediction model when they were associated with low paclitaxel clearance (1 SD below mean clearance) and subsequently tested in the validation set. Results: A genetic prediction model including 14 single-nucleotide polymorphisms (SNP) was developed on the training set. In the validation set, this model yielded a sensitivity of 95%, identifying most patients with low paclitaxel clearance correctly. The positive predictive value of the model was only 22%. The model remained associated with low clearance after multivariate analysis, correcting for age, gender, and hemoglobin levels at baseline (P = 0.02). Conclusions: In this first large-sized application of the DMET-platform for paclitaxel, we identified a 14 SNP model with high sensitivity to identify patients with low paclitaxel clearance. However, due to the low positive predictive value we conclude that genetic variability encoded in the DMET-chip alone does not sufficiently explain paclitaxel clearance.
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| 3. |
- de Graan, Anne-Joy M., et al.
(författare)
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CYP3A4*22 Genotype and Systemic Exposure Affect Paclitaxel-Induced Neurotoxicity
- 2013
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:12, s. 3316-3324
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239). Results: Exposure to paclitaxel ((log)AUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, C-max, or T->0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001). Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.
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| 4. |
- van der Veldt, Astrid A. M., et al.
(författare)
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Toward Prediction of Efficacy of Chemotherapy : A Proof of Concept Study in Lung Cancer Patients Using [11C]docetaxel and Positron Emission Tomography
- 2013
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:15, s. 4163-4173
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and a microdose of radiolabeled docetaxel ([11C]docetaxel). The objective of this study was to investigate whether a [11C]docetaxel PET microdosing study could predict tumor uptake of therapeutic doses of docetaxel.Experimental Design:Docetaxel-naïve lung cancer patients underwent 2 [11C]docetaxel PET scans; one after bolus injection of [11C]docetaxel and another during combined infusion of [11C]docetaxel and a therapeutic dose of docetaxel (75 mg·m−2). Compartmental and spectral analyses were used to quantify [11C]docetaxel tumor kinetics. [11C]docetaxel PET measurements were used to estimate the area under the curve (AUC) of docetaxel in tumors. Tumor response was evaluated using computed tomography scans.Results:Net rates of influx (Ki) of [11C]docetaxel in tumors were comparable during microdosing and therapeutic scans. [11C]docetaxel AUCTumor during the therapeutic scan could be predicted reliably using an impulse response function derived from the microdosing scan together with the plasma curve of [11C]docetaxel during the therapeutic scan. At 90 minutes, the accumulated amount of docetaxel in tumors was less than 1% of the total infused dose of docetaxel. [11C]docetaxel Ki derived from the microdosing scan correlated with AUCTumor of docetaxel (Spearman ρ = 0.715; P = 0.004) during the therapeutic scan and with tumor response to docetaxel therapy (Spearman ρ = −0.800; P = 0.010).Conclusions:Microdosing data of [11C]docetaxel PET can be used to predict tumor uptake of docetaxel during chemotherapy. The present study provides a framework for investigating the PET microdosing concept for radiolabeled anticancer drugs in patients.
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| 5. |
- de Graan, Anne-Joy M., et al.
(författare)
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Influence of Smoking on the Pharmacokinetics and Toxicity Profiles of Taxane Therapy
- 2012
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 18:16, s. 4425-4432
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cigarette smoke is known to interact with the metabolism of several anticancer drugs. It may also affect the incidence and severity of adverse events and efficacy of chemotherapy. The main objective of this study was to examine the effects of smoking on the pharmacokinetics and toxicities of patients treated with docetaxel or paclitaxel.Experimental Design: Smoking status, toxicity profiles, and pharmacokinetic parameters (calculated by nonlinear mixed-effect modeling population analysis) were determined in 566 patients (429 nonsmokers and 137 smokers) treated with docetaxel or paclitaxel.Results: Smokers treated with docetaxel showed less grade IV neutropenia (35% vs. 52%; P = 0.01) than nonsmokers. Smokers treated with paclitaxel had less grade III-IV leukopenia than nonsmokers (12% vs. 25%; P = 0.03), and the white blood cell (WBC) nadir was lower in nonsmokers (median, 2.7 x 10(9)/L; range, 0.05 x 10(9) to 11.6 x 10(9)/L) than in smokers (median, 3.3 x 10(9)/L; range 0.8 x 10(9) to 10.2 x 10(9)/L; P = 0.02). Of interest, significantly lower WBC counts and absolute neutrophil counts at baseline were seen in nonsmoking patients treated with paclitaxel (P = 0.0001). Pharmacokinetic parameters were similar in smokers and nonsmokers for both taxanes.Conclusion: Cigarette smoking does not alter the pharmacokinetic determinants of docetaxel and paclitaxel. Smokers treated with docetaxel and paclitaxel have less neutropenia and leukopenia, but further research is warranted to elucidate this potential protective effect.
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| 6. |
- Eechoute, Karel, et al.
(författare)
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A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients
- 2012
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 18:20, s. 5780-5787
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Imatinib minimal (trough) plasma concentrations after one month of treatment have shown a significant association with clinical benefit in patients with gastrointestinal stromal tumors (GIST). Considering that a retrospective pharmacokinetic analysis has also suggested that imatinib clearance increases over time in patients with soft tissue sarcoma and GIST, the primary aim of this study was to assess systemic exposure to imatinib at multiple time points in a long-term prospective population pharmacokinetic study. As imatinib is mainly metabolized in the liver, our secondary aim was to elucidate the potential effects of the volume of liver metastases on exposure to imatinib. Experimental Design: Full pharmacokinetic blood sampling was conducted in 50 patients with GIST on the first day of imatinib treatment, and after one, six, and 12 months. In addition, on day 14, and monthly during imatinib treatment, trough samples were taken. Pharmacokinetic analysis was conducted using a compartmental model. Volume of liver metastases was assessed by computed tomographic (CT) imaging. Results: After 90 days of treatment, a significant decrease in imatinib systemic exposure of 29.3% compared with baseline was observed (P < 0.01). For every 100 cm 3 increase of metastatic volume, a predicted decrease of 3.8% in imatinib clearance was observed. Conclusions: This is the first prospective pharmacokinetic study in patients with GIST, showing a significant decrease of approximately 30% in imatinib exposure after long-term treatment. This means that future "trough level - clinical benefit" analyses should be time point specific. GIST liver involvement, however, has a marginal effect on imatinib clearance.
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| 7. |
- van der Bol, Jessica M., et al.
(författare)
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A CYP3A4 Phenotype-Based Dosing Algorithm for Individualized Treatment of Irinotecan
- 2010
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 16:2, s. 736-742
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Irinotecan, the prodrug of SN-38, is extensively metabolized by cytochrome P450-3A4 (CYP3A4). A randomized trial was done to assess the utility of an algorithm for individualized irinotecan dose calculation based on a priori CYP3A4 activity measurements by the midazolam clearance test. Experimental Design: Patients were randomized to receive irinotecan at a conventional dose level of 350 mg/m(2) (group A) or doses based on an equation consisting of midazolam clearance, gamma-glutamyl-transferase, and height (group B). Pharmacokinetics and toxicities were obtained during the first treatment course. Results: Demographics of 40 evaluable cancer patients were balanced between both groups, including UGT1A1*28 genotype and smoking status. The absolute dose of irinotecan ranged from 480 to 800 mg in group A and 380 to 1,060 mg in group B. The mean absolute dose and area under the curve of irinotecan and SN-38 were not significantly different in either group (P > 0.18). In group B, the interindividual variability in the area under the curve of irinotecan and SN-38 was reduced by 19% and 25%, respectively (P > 0.22). Compared with group A, the incidence of grades 3 to 4 neutropenia was >4-fold lower in group B (45 versus 10%; P = 0.013). The incidence of grades 3 to 4 diarrhea was equal in both groups (10%). Conclusions: Incorporation of CYP3A4 phenotyping in dose calculation resulted in an improved predictability of the pharmacokinetic and toxicity profile of irinotecan, thereby lowering the incidence of severe neutropenia. In combination with UGT1A1*28 genotyping, CYP3A4 phenotype determination should be explored further as a strategy for the individualization of irinotecan treatment.
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